Anxiety disorders, including post-traumatic stress disorder (PTSD), affect about 40 million American adults each year (18% of the population) and thus represent a major health problem. The main brain system involved in fear and anxiety is the amygdala, including its connections with discrete forebrain and brainstem regions. Behavioral, electrophysiological, pharmacological, and molecular biological studies of emotional learning in the amygdala have elucidated many of the neural circuits and mechanisms involved in normal fear and anxiety, and have suggested ways in which alterations in these mechanisms can provoke anxiety disorders. However, much more needs to be learned about these mechanisms before more effective treatments can be developed. The proposed study is the continuation of a long-term investigation of the synaptic organization of the basolateral nuclear complex of the amygdala (BLC) whose main goal is to elucidate the basic chemical neuroanatomy of amygdalar systems involved in emotional memory and learning. In the present project we will focus on the synaptic organization of inputs from dopaminergic systems of the brainstem, cholinergic and GABAergic inputs from the basal forebrain, and glutamatergic inputs from the medial prefrontal cortex. In all cases these inputs will be studied in relation to specific neuronal subpopulations which have been identified in previous project periods of this grant. These studies will use both rodents and monkeys as experimental animals. Although rodents have been used in most functional studies of emotional learning, it is important to determine if the synaptic organization of the nonhuman primate amygdala is similar, since it is more likely to resemble that of humans. This should allow information about the organization of neuromodulatory inputs to primate BLC neurons to be translated into the development of novel pharmacological therapies to modulate the activity of the human amygdala in neuropsychiatric and epileptic disorders. Studies in the rat BLC will utilize light and electron microscopy to: 1) analyze its innervation by cholinergic and GABAergic neurons of the basal forebrain; 2) study the cellular and subcellular localization of D1 and D2 receptors using anatomical and physiological approaches, and 3) investigate medial prefrontal and temporal cortical inputs and their interactions with dopaminergic inputs. Studies in the monkey will utilize light and electron microscopy to analyze the synaptic organization and dopaminergic innervation of pyramidal cells, somatic-targeting interneurons, and dendritic-targeting interneurons in the BLC.